While human prostate cancer genetics are advancing at rapid pace, critical questions about genetic susceptibility and prevention remain unanswered. This study focuses on the roles of DNA repair and genomic instability in human prostate carcinogenesis. The incidence of prostate cancer increases with age; more than 75% of all prostate cancers are diagnosed in men over age 65. Incidence and mortality rates are higher for African-American men than white men. The mechanisms involved are not yet fully understood. The contributors to the racial/ethnic disparity in prostate cancer risk include genetic background, lifestyle, and environmental factors. The proposed molecular epidemiology research will include 800 newly diagnosed prostate cancer cases (200 African American; 600 Caucasian) and 800 controls, frequency-matched to cases on race and age. A risk and dietary questionnaire will be used to collect data on other prostate cancer risk factors. The specific aims of the proposed research are: (1) To test the hypothesis that defective/deficient DNA repair activity is associated with prostate cancer risk. (2) To evaluate the differences in genetic predisposition to prostate cancer due to polymorphisms of susceptibility genes. (3) To investigate the complex interactions in prostate carcinogenesis. This evaluation aims to identify high-risk profile and targets for cancer prevention. (4) To explore the relationship between specific DNA repair profile and chromosomal imbalances in prostate tumor cells.